Speaker Name Speaker Title Speaker Affiliation

1. You are the Keyto HPV Cancer PreventionUnderstanding the Burden of HPV Disease, the Importance of the HPV Vaccine Recommendation, and Communicating about HPV Vaccination Speaker Name Speaker Title Speaker Affiliation {Updated August 5, 2014; Replace with date of Presentation}

2. Disclosure • Please add any financial disclosures or conflicts of interest to this slide

3. Summary Stagnant HPV vaccination rates are leaving another cohort of boys and girls vulnerable to devastating HPV cancers. Vaccination could prevent most of these cancers. Provided in this presentation is up-to-date information on HPV infection, HPV-related disease, and HPV cancers. HPV vaccine information and recommendations, as well as HPV vaccine safety and impact, are reviewed. The presentation also provides evidence-based suggestions for successful HPV vaccine communication with patients and their parents, as well as the current HPV vaccine communication resources available from CDC.

4. Objectives • Define the importance of HPV vaccination for cancer prevention and the rationale for vaccinating at ages 11 or 12. • List the indications for HPV vaccine for girls and for boys. • Provide useful and compelling information about HPV vaccine to parents to aid in making the decision to vaccinate. • Locate resources relevant to current immunization practice.

5. Understanding the Burden HPV Infection & Disease

6. HPV Types Differ in their Disease Associations Mucosal sites of infection Cutaneous sites of infection ~ 80 Types ~40 Types High risk (oncogenic)HPV 16, 18 Low risk (non-oncogenic)HPV 6, 11 Cervical Cancer Anogenital Cancers Oropharyngeal Cancer Cancer Precursors Low Grade Cervical Disease Genital Warts Laryngeal Papillomas Low Grade Cervical Disease “Common” Hand and Foot Warts

7. HPV Infection • Most females and males will be infected with at least one type of HPV at some point in their lives • Estimated 79 million Americans currently infected • 14 million new infections/year in the US • HPV infection is most common in people in their teens and early 20s • Most people will never know that they have been infected Jemal A et al. J Natl Cancer Inst2013;105:175-201

8. Numbers of Cancers and Genital Warts Attributed to HPV Infections, U.S. CDC. Human papillomavirus (HPV)-associated cancers. Atlanta, GA: US Department of Health and Human Services, CDC; 2013. Available at http://www.cdc.gov/cancer/hpv/statistics/cases.htm

9. Cancers Attributed to HPV, U.S. CDC, United States Cancer Statistics (USCS), 2006-2010

10. Average Number of New Cancers Probably Caused by HPV, by Sex, United States 2006-2010 Penisn=7008% Vaginan=6003% Vulva n=2,200 13% Anusn=2,60015% Anusn=1,40015% Oropharynxn=1,80010% Oropharynxn=7,20077% Cervixn=10,40059% Men (n = 9,300) Women (n = 17,600) CDC, United States Cancer Statistics (USCS), 2006-2010

11. How Many Cancers Are Linked with HPV Each Year?

12. Cervical Cancer • Cervical cancer is the most common HPV-associated cancer among women • 500,000+ new cases and 275,000 attributable deaths world-wide in 2008 • 11,000+ new cases and 4,000 attributable deaths in 2011 in the U.S. • 37% cervical cancers occur in women who are between the ages of 20 and 44 • 13% (or nearly 1 in 8) between 20 and 34 • 24% ( or nearly 1 in 4) between 35 and 44 CDC. HPV–associated cancers—US, 2004–2008. MMWR 2012;61(15):258–261. Cervical Cancer Counts by Age. US Cancer Statistics data from 2010, CDC.gov.

13. HPV-Associated Cervical Cancer Rates by Race and Ethnicity, United States, 2004–2008 Watson et al. Human papillomavirus-associated cancers—United States, 2004-2008. MMWR 2012;61:258-261.

14. HPV-Associated Cervical Cancer Incidence Rates by State, United States, 2006-2010 HPV-Associated Cervical Cancer Incidence Rates by State, United States, 2004–2008 www.cdc.gov/cancer/npcr

15. Rates of HPV-Associated Cancer and Median Age at Diagnosis Among Females, United States, 2004–2008 Rates of HPV-Associated Cancer and Median Age at Diagnosis Among Females in the United States, 2004–2008 *The vaginal cancer statistics for women between the ages of 20 and 39 is not shown because there were fewer than 16 cases. Watson et al. Human papillomavirus-associated cancers—United States, 2004-2008. MMWR 2012;61:258-261.

16. Annual Report to the Nation on the Status of Cancer: HPV-Associated Cancers • From 2000 to 2009, oral cancer rates increased • 4.9% for Native American men • 3.9% for white men • 1.7% for white women • 1% for Asian men • Anal cancer rates doubled from 1975 to 2009 • Vulvar cancer rates rose for white and African-American women • Penile cancer rates increased among Asian men • Jemal A et al. J Natl Cancer Inst 2013;105:175-201

17. Rates of HPV-Associated Cancer and Median Age at Diagnosis Among Males, United States, 2004–2008 Rates of HPV-Associated Cancer and Median Age at Diagnosis Among Males in the United States, 2004–2008 *The penile cancer statistics for men between the ages of 20 and 39 is not shown because there were fewer than 16 cases. Watson et al. Human papillomavirus-associated cancers—United States, 2004-2008. MMWR 2012;61:258-261.

18. HPV-Associated Anal Cancer Rates by Race and Ethnicity, United States, 2004–2008 HPV-Associated Anal Cancer Ratesby Race and Ethnicity, United States, 2004–2008 Watson et al. Human papillomavirus-associated cancers—United States, 2004-2008. MMWR 2012;61:258-261.

19. HPV-Associated Oropharyngeal Cancer Rates by Race and Ethnicity, United States, 2004–2008 HPV-Associated Oropharyngeal Cancer Ratesby Race and Ethnicity, United States, 2004–2008 Watson et al. Human papillomavirus-associated cancers—United States, 2004-2008. MMWR 2012;61:258-261.

20. Without vaccination, annual burden of genital HPV-related disease in U.S. females: 4,000 cervical cancer deaths 10,846 new cases of cervical cancer 330,000 new cases of HSIL: CIN2/3 (high grade cervical dysplasia) 1 million new cases of genital warts 1.4 million new cases ofLSIL: CIN1 (low grade cervical dysplasia) 3 million cases and $7 billion American Cancer Society. 2008; SchiffmanArch Pathol Lab Med. 2003; Koshiol Sex Transm Dis. 2004; Insinga, Pharmacoeconomics, 2005

21. Evidence-Based HPV Prevention HPV Vaccine

22. HPV Prophylactic Vaccines • Recombinant L1 capsid proteins that form “virus-like” particles (VLP) • Non-infectious and non-oncogenic • Produce higher levels of neutralizing antibody than natural infection HPV Virus-Like Particle

23. HPV Vaccine

24. Evolution of recommendations for HPV vaccination in the United States Quadrivalent Routine, females 11 or 12 yrs* and 13-26 yrs not previously vaccinated Quadrivalent or Bivalent Routine, females 11 or 12 yrs* and 13-26 yrs not previously vaccinated Quadrivalent Routine, males 11 or 12 yrs* and 13-21 yrs not previously vaccinated May be given, 22-26 yrs** Quadrivalent May be given, males 9-26 yrs* June October Quadrivalent (HPV 6,11,16,18) vaccine; Bivalent (HPV 16,18) vaccine Can be given starting at 9 years of age; ** For MSM and immunocompromised males, quadrivalent HPV vaccine through 26 years of age

25. ACIP Recommendation and AAP Guidelines for HPV Vaccine • Routine HPV vaccination recommended for both males and females ages 11-12 years • Also ages 13-21 years for males; 13-26 for females • Vaccine can be given starting at age 9 years of age for both males and females; vaccine can be given ages 22-26 years for males CDC. Quadrivalent Human Papillomavirus Vaccine: Recommendations of ACIP. MMWR 2007;56(RR02):1-24.

26. HPV Vaccination Schedule • ACIP Recommended schedule is 0, 1-2*, 6 months • Following the recommended schedule is preferred • Minimum intervals • 4 weeks between doses 1 and 2 • 12 weeks between doses 2 and 3 • 24 weeks between doses 1 and 3 • Administer IM CDC. Quadrivalent Human Papillomavirus Vaccine: Recommendations of ACIP. MMWR 2007;56(RR02):1-24.

27. HPV Vaccine is an Anti-Cancer Vaccine Reduction in prevalence of vaccine-type HPV by 56% in girls age 14-19 with vaccination rate of just ~30% Our low vaccination rates will lead to 50,000 girls developing cervical cancer – that would be prevented if we reach 80% vaccination rates For every year we delay increasing vaccination rates to this level, another 4,400 women will develop cervical cancer Markowitz et al. JID 2013;208:385-393. CDC unpublished model – H. Chesson et al - for girls in US <13 at present, diff. betw 30% vs. 80% 3-dose coverage, lifetime cerv. ca. risk

28. HPV Vaccine Is Safe, Effective, and Provides Lasting Protection • HPV Vaccine is SAFE • Safety studies findings for HPV vaccine similar to safety reviews of MCV4 and Tdap vaccines • HPV Vaccine WORKS • High grade cervical lesions decline in Australia (80% of school aged girls vaccinated) • Prevalence of vaccine types declines by more than half in United States (33% of teens fully vaccinated) • HPV Vaccine LASTS • Studies suggest that vaccine protection is long-lasting; no evidence of waning immunity Garland et al, Prev Med 2011; Ali et al, BMJ 2013; Markowitz JID 2013; Nsouli-Maktabi MSMR 2013

29. HPV Vaccine Safety

30. HPV Vaccine Safety Data Sources • Post-licensure safety data (VAERS)1 • Post-licensure observational comparative studies (VSD)2 • Ongoing monitoring by CDC and FDA • Post-licensure commitments from manufacturers • Vaccine in pregnancy registries • Long term follow-up in Nordic countries • Official reviews • WHO’s Global Advisory Committee on Vaccine Safety 3 • Institute of Medicine’s report on adverse effects and vaccines, 20114 1Vaccine Adverse Events Reporting System, http://vaers.hhs.gov/index 2Vaccine Safety Datalink, http://www.cdc.gov/vaccinesafety/Activities/VSD.html 3http://www.who.int/vaccine_safety/Jun_2009/en/ 4http://www.iom.edu/Reports/2011/Adverse-Effects-of-Vaccines-Evidence-and-Causality.aspx

31. HPV Vaccine Safety Monitoring The Vaccine Adverse Event Reporting System (VAERS) • An early warning public health system where people can report adverse health events following vaccination, that helps CDC and FDA detect possible new, unexpected, or increased trends in reported adverse events The Vaccine Safety Datalink (VSD) • Collaboration between CDC and several healthcare organizations which uses de-identified health records to monitor and evaluate adverse events following vaccination The Clinical Immunization Safety Assessment (CISA) • Collaboration between CDC and several medical research centers in the United States to conduct research to understand how adverse events might be caused by vaccines http://www.cdc.gov/vaccinesafety/vaccines/HPV/Index.html#monitor

32. HPV Vaccine Safety Monitoring: VAERS • No new safety concerns have been identified in post-licensure vaccine safety surveillance among male or female recipients of HPV4 vaccine • Among the 7.9% of reports coded as “serious”, most frequently cited are headache, nausea, vomiting, fatigue, dizziness, syncope, generalized weakness • Syncope continues to be a frequently reported adverse event following immunization among adolescents • Adherence to a 15-minute observation period after vaccination is encouraged 32 http://www.cdc.gov/vaccinesafety/vaccines/HPV/Index.html#monitor

33. Trends in Total and Serious Female HPV4 Vaccine Reports to VAERS by Year, June 2006 – March 2013 (N=21,194) 33 MMWR 2013;62:591-595

34. Markowitz L, ACIP presentation, June 2013 Gee J et al, Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine 2011;29:8279-8284. HPV4 Rapid Cycle Analysis Results:Vaccine Safety Datalink • VSD active surveillance of HPV4 among females confirmed no significant risk for any of the pre-specified adverse events after vaccination • GBS, seizures, syncope, appendicitis, stroke, venous thromboembolism, and other allergic reactions • Additional study is needed for a possible non-statistical association between HPV4 and venous thromboembolism • No increase in rate of anaphylaxis following HPV4 as compared to previous VSD studies • Extended follow-up for GBS and stroke among females 9-26 years of age found no increased risk

35. Institute of Medicine ReportAdverse Effects of Vaccines: Evidence and Causality • IOM reviewed possible associations between adverse health events and eight vaccines • Evidence “favors acceptance” of a causal relationship between HPV vaccine and anaphylaxis (yeast and latex components) • Evidence “convincingly supports” a causal relationship between the injection of a vaccine and syncope • Inadequate evidence was found for causal relationships between HPV vaccination and 12 other specific health events studied Institute of Medicine. Adverse Effects of Vaccines: Evidence and Causality. Washington DC. The National Academies Press, 2012.

36. Inadvertent Administration of HPV Vaccine during Pregnancy • No safety concerns* raised by HPV4 in pregnancy registry • CDC/FDA continue to monitor the safety of HPV vaccine, including reports in pregnant women through VAERS • A retrospective analysis of pregnancy-associated HPV4 VAERS reports is in progress (2005-2012) • >85% of reports were submitted from the Merck Pregnancy Registry so anticipate a similar safety profile • For VSD, descriptive data of adverse events following inadvertent exposure to HPV4 during pregnancy by 2015 *death, life-threatening illness, hospitalization, prolongation of existing hospitalization, persistent or significant disability, congenital malformations 36

37. HPV Vaccine Impact

38. HPV VaccineDuration of Immunity • Studies suggest that vaccine protection is long-lasting; no evidence of waning immunity • Available evidence indicates protection for at least 8-10 years • Multiple cohort studies are in progress to monitor the duration of immunity Romanowski B. Long term protection against cervical infection with the human papillomavirus: review of currently available vaccines. Hum Vaccin. 2011 Feb;7(2):161-9.

39. Monitoring Impact of HPV Vaccine Programs: HPV-associated Outcomes

40. HPV Vaccine Impact:HPV Prevalence Studies • NHANES Study • National Health and Nutrition Examination Survey (NHANES) data used to compare HPV prevalence before the start of the HPV vaccination program with prevalence from the first four years after vaccine introduction • In 14-19 year olds, vaccine-type HPV prevalence decreased 56 percent, from 11.5 percent in 2003-2006 to 5.1 percent in 2007-2010 • Other age groups did not show a statistically significant difference over time • The research showed that vaccine effectiveness for prevention of infection was an estimated 82 percent Cummings T, Zimet GD, Brown D, et al. Reduction of HPV infections through vaccination among at-risk urban adolescents. Vaccine. 2012; 30:5496-5499.

41. Prevalence of HPV 6, 11,16, 18* in CervicovaginalSwabs, by Age Group, NHANES, 2003-2006 and 2007-2010, U.S. 56% decline *weighted prevalence Markowitz, et al. Reduction in HPV prevalence among young women following HPV vaccine introduction in the United States, NHANES, 2003-2010. J Infect Dis 2103 41

42. HPV Vaccine Impact:HPV Prevalence Studies, continued • Clinic-Based Studies • Significant decrease from 24.0% to 5.3% in HPV vaccine type prevalence in at-risk sexually active females 14-17 years of age attending 3 urban primary care clinics from 1999-2005, compared to a similar group of women who attended the same 3 clinics in 2010 • Significant declines in vaccine type HPV prevalence in both vaccinated and unvaccinated women aged 13-26 years who attended primary care clinics from 2009-2010 compared to those from the pre-vaccine period (2006-2007) Kahn JA, Brown DR, Ding L, et al. Vaccine-Type Human Papillomavirus and Evidence of Herd Protection After Vaccine Introduction. Pediatrics. 2012; 130:249-56.

43. Impact of HPV vaccination in Australia Proportion of Australian born females and males diagnosed as having genital warts at first visit, by age group, 2004-11 Females Males Ali, et al., Genital warts in young Australians five years into national human papillomavirus vaccination programme: national surveillance data. British Med J 2013;346:f2032 43

44. Impact of HPV Vaccine on HPV 16/18 Precancers • CIN2+ cases women 18 to 31 years of age were reported from pathology laboratories in 5 states from 2008 to 2011 • Of 5083 CIN2+ cases, 3855 had vaccination histories investigated, and 1900 had vaccine history documented • Among women with CIN2+ who had started HPV vaccine more than 24 months before their Pap smear, there was a significant reduction in HPV 16/18-related lesions • These results suggest an early impact of the HPV vaccine on vaccine-type precancers Powell S, et al, Impact of human papillomavirus (HPV) vaccination on HPV 16/18-related prevalence in precancerous cervical lesions. Vaccine 2012;31:109-113 44

45. Anogenital Wart Prevalence per 1000 person-years, US Private Insurance Enrollees, by Age, 2003-2010 Males Females Prevalence per 1000 Person-years 25-29 20-24 20-24 30-34 25-29 • 35-39 30-34 15-19 35-39 15-19 10-14 10-14 Flagg, et al. AJPH 2013

46. Impact of Bivalent HPV Vaccine on Oral HPV Infection • Of 7,466 women 18-25 years of age randomized to receive HPV vaccine or hepatitis A vaccine, 5,840 provided oral specimens at the final 4-year study visit • Oral prevalence of identifiable mucosal HPV was relatively low (1.7%) • There were 15 HPV 16/18 infections in the hepatitis A comparison group and 1 in the HPV vaccine group, for an estimated vaccine efficacy of 93.3% • These results suggest that the vaccine provides strong protection against oral HPV 16/18 infection and may prevent HPV 16/18-associated oropharyngeal cancers Herrero R, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLOS ONE 2013;8:e68329 46

47. HPV Vaccine coverage

48. Strong Start? Adolescent Immunization Coverage, US 13-17 year olds National Immunization Survey-Teen (NIS-Teen) 2006 vs. 2007 CDC. National and State Vaccination Coverage Among Adolescents Aged 13–17 Years — United States, 2012 MMWR 2013; 62(34);685-693.

49. Adolescent Vaccination CoverageUnited States, 2006-2013 MMWR 2014; 63(29);625-633.

50. Impact of Eliminating Missed Opportunities by Age 13 Years in Girls Born in 2000 Missed opportunity: Healthcare encounter when some, but not all ACIP-recommended vaccines are given. HPV-1: Receipt of at least one dose of HPV. MMWR. 63(29);620-624.